Functional rescue of misfolding ABCA3 mutations by small molecular correctors.
Hum Mol Genet
; 27(6): 943-953, 2018 03 15.
Article
em En
| MEDLINE
| ID: mdl-29325094
ABSTRACT
Adenosine triphosphate (ATP)-binding cassette subfamily A member 3 (ABCA3), a phospholipid transporter in lung lamellar bodies (LBs), is essential for the assembly of pulmonary surfactant and LB biogenesis. Mutations in the ABCA3 gene are an important genetic cause for respiratory distress syndrome in neonates and interstitial lung disease in children and adults, for which there is currently no cure. The aim of this study was to prove that disease causing misfolding ABCA3 mutations can be corrected in vitro and to investigate available options for correction. We stably expressed hemagglutinin (HA)-tagged wild-type ABCA3 or variants p.Q215K, p.M760R, p.A1046E, p.K1388N or p.G1421R in A549 cells and assessed correction by quantitation of ABCA3 processing products, their intracellular localization, resembling LB morphological integrity and analysis of functional transport activity. We showed that all mutant proteins except for M760R ABCA3 were rescued by the bithiazole correctors C13 and C17. These variants were also corrected by the chemical chaperone trimethylamine N-oxide and by low temperature. The identification of lead molecules C13 and C17 is an important step toward pharmacotherapy of ABCA3 misfolding-induced lung disease.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doenças Pulmonares Intersticiais
/
Transportadores de Cassetes de Ligação de ATP
/
Mutação de Sentido Incorreto
/
Deficiências na Proteostase
/
Metilaminas
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article